In sickness and in health: The many roles of the minichromosome maintenance proteins

Neves, Henrique; Kwok, Hang Fai

doi:10.1016/j.bbcan.2017.06.001

Cited by 32 publications

(40 citation statements)

References 235 publications

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“…In normal cells, cell proliferation is tightly regulated by the binding of DNA licensing factors such as CDC6, Cdt1 and Minichromosome Maintenance proteins (MCM) proteins (MCM2-7) onto DNA replication initiation sites. We, along with others, have previously observed the high expression of CDC6, CDT1 and MCM2-7 proteins in breast cancer progression [ 2 , 3 , 4 ]. Alterations in the expression profiles of the licensing proteins have been linked to various aspects of cancer [ 5 , 6 ] such as cancer cell proliferation [ 7 , 8 ] and cancer invasion [ 9 ].…”

Section: Introductionmentioning

confidence: 69%

“…Depletion of some of these licensing factors, in vitro, is known to reduce cell proliferation as well as induce programmed cell death [ 10 ]. Therefore, DNA licensing factors have been reported as important prognostic markers in cancers such as lung, prostrate, and bladder cancers [ 2 ]. Reduction of MCM proteins in cancer cells is known to induce sensitivity to drugs such as aphidicolin, camptothecin, hydroxyurea, etc., and thereby promote an anti-proliferative effect [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Depletion of MCM10 has been observed to regulate the turnover of DNA polymerase-α [ 15 ]. MCM10 is also known to interact with other replication protein complexes such as the MCM2-7 complex, Replication protein A and Proliferating cell nuclear antigen (PCNA), thereby maintaining a steady state during DNA replication [ 2 ]. Consequently, dysregulation of MCM10 protein may lead to genomic instability and replication stress, which can, in turn, induce tumorigenesis [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer

Mahadevappa

Neves

Yuen

et al. 2018

Cancers

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Breast cancer is one of the most common malignancies in women worldwide. In breast cancer, the cell proliferation rate is known to influence the cancer malignancy. Recent studies have shown that DNA replication initiation/licensing factors are involved in cancer cell proliferation as well as cancer cell migration and invasion. Licensing factors have also been reported as important prognostic markers in lung, prostrate, and bladder cancers. Here, we studied the role of MCM10, a novel licensing factor, in breast cancer progression. From the public database, NCBI, we investigated six independent breast cancer patient cohorts, totaling 1283 patients. We observed a significant association between high MCM10 mRNA expression with tumor grading and patients’ survival time. Most importantly, using breast cancer cohorts with available treatment information, we also demonstrated that a high level of MCM10 is associated with a better response to conventional treatment. Similarly, in in vitro studies, the expression level of MCM10 in breast cancer cell lines is significantly higher compared to paired normal breast epithelium cells. Knockdown of MCM10 expression in the cancer cell line showed significantly decreased tumorigenic properties such as cell proliferation, migration and anchorage independence. The MCF7 breast cancer cell line, after MCM10 expression knockdown, showed significantly decreased tumorigenic properties such as cell proliferation, migration, and anchorage independent growth. Mechanistically, MCM10 expression is observed to be regulated by an Estrogen Receptor (ER) signaling pathway, where its expression is suppressed by the inhibition of the ER or serum withdrawal. Our results suggest that MCM10 plays an important role in breast cancer progression and is a potential prognostic/predictive biomarker and therapeutic target for breast cancer patients.

show abstract

Section: Introductionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer

Mahadevappa

Neves

Yuen

et al. 2018

Cancers

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“…Expression levels of Mcm subunits are down-regulated in differentiated somatic cells in keeping with its function in cell proliferation (Gupta and Brosh, 2008 ). On the other hand, enhanced expression of Mcm proteins have been reported in many cancer cells derived from patients (Neves and Kwok, 2017 ). The roles of the Mcm proteins in cancer progression have been linked to at least two cancer hallmarks including enhanced proliferation and regulation of replicative stress.…”

Section: Dna Helicases An Emerging Target For Cancer Therapymentioning

confidence: 99%

The Human Replicative Helicase, the CMG Complex, as a Target for Anti-cancer Therapy

Seo

Kang

2018

Front. Mol. Biosci.

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DNA helicases unwind or rearrange duplex DNA during replication, recombination and repair. Helicases of many pathogenic organisms such as viruses, bacteria, and protozoa have been studied as potential therapeutic targets to treat infectious diseases, and human DNA helicases as potential targets for anti-cancer therapy. DNA replication machineries perform essential tasks duplicating genome in every cell cycle, and one of the important functions of these machineries are played by DNA helicases. Replicative helicases are usually multi-subunit protein complexes, and the minimal complex active as eukaryotic replicative helicase is composed of 11 subunits, requiring a functional assembly of two subcomplexes and one protein. The hetero-hexameric MCM2-7 helicase is activated by forming a complex with Cdc45 and the hetero-tetrameric GINS complex; the Cdc45-Mcm2-7-GINS (CMG) complex. The CMG complex can be a potential target for a treatment of cancer and the feasibility of this replicative helicase as a therapeutic target has been tested recently. Several different strategies have been implemented and are under active investigations to interfere with helicase activity of the CMG complex. This review focuses on the molecular function of the CMG helicase during DNA replication and its relevance to cancers based on data published in the literature. In addition, current efforts made to identify small molecules inhibiting the CMG helicase to develop anti-cancer therapeutic strategies were summarized, with new perspectives to advance the discovery of the CMG-targeting drugs.

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“… 1 All eukaryotic organisms, including human, possess 6 highly related MCM genes – MCM2–7. 2 These genes have been shown to play an important role in cancer development and have been linked to various cancer hallmarks, 3 especially for enhanced proliferation in cancer. Indeed, MCM genes were dysregulated in many types of cancer.…”

Section: Introductionmentioning

confidence: 99%

Expression of minichromosome maintenance genes in renal cell carcinoma

Zhong¹,

Chen²,

Neves³

et al. 2017

CMAR

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Minichromosome maintenance (MCM) proteins play an essential role in DNA replication. They have been shown to be overexpressed in various types of cancer. However, the role of this family in renal cell carcinoma (RCC) is widely unknown. In this study, we have identified a number of RCC datasets in the Gene Expression Omnibus database and also investigated the correlation between the expression levels of MCM genes and clinicopathological parameters. We found that the expression levels of MCM genes are positively correlated with one another. Expression levels of MCM2, MCM5, MCM6, and MCM7, but not of MCM3 and MCM4, were higher in RCC compared to paired adjacent normal tissue. Only the expression level of MCM4, but not of other MCMs, was positively correlated with tumor grade. In addition, a high-level expression of MCM2 in either primary tumor or metastases of RCC predicted a shorter disease-free survival time, while a high-level expression of MCM4 or MCM6 in primary tumor was also associated with poorer disease-free survival. Interestingly, we also demonstrated that patients with their primary RCC overexpressing 2 or more MCM genes had a shorter disease-free survival time, while those with RCC metastases overexpressing 3 or more MCM genes had a shorter disease-free survival. Importantly, we also demonstrated that overexpression of MCM genes is an independent predictor for survival in RCC patients. Our results suggest that MCM2–7 genes may be an important prognostic marker for patients with RCC.

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In sickness and in health: The many roles of the minichromosome maintenance proteins

Cited by 32 publications

References 235 publications

DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer

DNA Replication Licensing Protein MCM10 Promotes Tumor Progression and Is a Novel Prognostic Biomarker and Potential Therapeutic Target in Breast Cancer

The Human Replicative Helicase, the CMG Complex, as a Target for Anti-cancer Therapy

Expression of minichromosome maintenance genes in renal cell carcinoma

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